Project Summary Sudden infant death syndrome (SIDS) and sudden unexplained death in childhood (SUDC), which we study together under the rubric of sudden unexpected death in pediatrics (SUDP), is a major cause of infant and child mortality. While Safe Sleep efforts aim to minimize risks in the sleep environment in SIDS, it is recognized that affected children also possess intrinsic vulnerabilities that increase their susceptibility to sudden death. As external factors have been addressed, the persistence of SUDP attests to the significance of these intrinsic vulnerabilities. SUDP has long been considered ?idiopathic,? like other conditions with elusive and likely multifactorial etiologies. Our group approaches SUDP as a constellation of undiagnosed diseases. We hypothesize that the intrinsic biological factors leading to SUDP include neurodevelopmental, epilepsy-related, cardiac, metabolic, respiratory, and infectious mechanisms, and that these mechanisms have a discoverable genetic basis. We take a multidisciplinary approach that mirrors undiagnosed disease programs, with extensive phenotyping and comprehensive genomic analysis to identify unrecognized disease mechanisms responsible for SUDP. Our group has previously found serotonin deficits in the brainstem of SIDS infants, malformations of the hippocampus in SIDS and SUDC cases, and shown that our diagnostic approach increases the likelihood of implicating natural causes in the assessment of these deceased children. The research in this application seeks preliminary data on novel genes and genomic mechanisms underlying sudden death through an analysis informed by our program's approach to phenotyping. The proposed research will investigate whether a complex genetic architecture plays a major role in SUDP. This hypothesis will be pursued by combining rich phenotypic data from SUDP cases with exome sequencing analysis. We will ascertain and comprehensively phenotype SUDP cases and their families (Aim 1), and then analyze exome data from these well-phenotyped proband-parent trios, to determine genetic mechanisms associated with SUDP (Aim 2). A highly novel aspect of this research is the opportunity to gain population- based insights due to the unprecedented forensic-academic partnership we have established with the Massachusetts Office of the Chief Medical Examiner (OCME) to assess all children dying suddenly and unexpectedly under the age of 3 years in Massachusetts. The potential impact of this research is the elucidation of genetic mechanisms involved in sudden unexplained deaths in children under the age of three years. This research carries the further promise of contributing to advancements in specific predictive algorithms and genetic markers for infants at risk for SUDP, and advancing the forensic molecular autopsy in establishing a major cause of mortality. The preliminary data gained in this research will lead to the refinement of hypotheses to be explored in future research.